Synthesis of 3, 4-O-Isopropylidene-(3S,4S)-dihydroxy-(2A,5R)-bis(diphenylphosphino)hexane and Its Application in Rh-Catalyzed Highly Enantioselective Hydrogenation of Enamides

Full text of DOI:10.1021/jo0004613

J . Org. Chem. 2000, 65, 5871-5874
5871
Syn th esis of 3, 4-O-Isop r op ylid en e-
(3S,4S)-d ih yd r oxy-(2R,5R)-
bis(d ip h en ylp h osp h in o)h exa n e a n d Its
Ap p lica tion in Rh -Ca ta lyzed High ly
En a n tioselective Hyd r ogen a tion of
En a m id es
Wenge Li and Xumu Zhang*
Department of Chemistry, 152 Davey Laboratory,
The Pennsylvania State University,
F igu r e 1.
University Park, Pennsylvania 16802
bisphosphine ligand for highly efficient Rh-catalyzed
asymmetric hydrogenation as well as the principle of
conformational analysis for designing effective chiral
ligands.
xumu@chem.psu.edu
Received March 28, 2000
Development of chiral phosphine ligands has played a
significant role in transition metal-catalyzed asymmetric
synthesis and has attracted much attention of synthetic
chemists.1 Chiral C2-symmetric diphosphines are of
special interest due to their effectiveness in many asym-
metric reactions.2 Ligands such as DIOP,3 DIPAMP,4
Chiraphos,5 Skewphos,6 BPPM,7 DEGPhos,8 BINAP,9
DuPhos,10 BPE,10 BICP,11 and PennPhos12 are some
representative examples of 1,2-, 1,3-, and 1,4-diphos-
phines which form a five-, six-, and seven-membered ring
with transition metals. Due to the limitation of existing
chiral ligands in their activity and enantioselectivity for
different reactions and substrates, design of new chiral
phosphines is still an important and challenging goal.
Herein, we report development of a new chiral 1,4-
The relationship between conformations of a chiral
catalyst and reaction enantioselectivity has been exten-
sively studied. In general, high asymmetric induction is
attributed to a well-defined chiral conformation of the
metal-ligand chelating compound.13 For Rh-catalyzed
asymmetric hydrogenation, orientation of phenyl groups
of chiral diphenylphosphino ligands dictates the enanti-
oselectivity.14 Ligands such as BINAP, DIOP, BPPM,
DEGPhos, Chiraphos, Skewphos, and BICP form metal
complexes in which one chelate ring conformation is
considered to be most stable. However, metal complexes
with these ligands have different degrees of conforma-
tional flexibility. Generally, a seven-membered ring metal
complex is more conformationally flexible than six- and
five-membered ring metal species. The conformational
flexibility in a chiral catalyst sometimes leads to erosion
of enantioselectivity. For example, a metal-DIOP com-
plex is conformationally flexible and the stereogenic
centers may be too far from the substrate (transfer of
backbone chirality to the phenyl groups on the phosphine
goes through a methylene group).
To overcome this drawback, Kagan synthesized ligand
2 in which stereogenic centers are closer to the phos-
phines.15 Unfortunately, enantioselectivity for Rh-cata-
lyzed asymmetric hydrogenation of dehydroamino acids
and enamides with ligand 2 is lower compared to the
corresponding Rh-DIOP species.15 We rationalized that
the two methyl groups in 2 may locate in axial positions
in the chelate ring resulting in an unfavorable conforma-
tion for enantioselective asymmetric reactions. To develop
an effective asymmetric catalyst, we decided to invert the
configuration of two stereogenic centers in 2 to make
chiral ligand 3 (R, S, S,R)-DIOP*16 so that methyl groups
along with all other substituents orient in equatorial
positions.17 While this hypothesis needs to be approved,
(1) Brunner, H.; Zettlmeier, W. Handbook of Enantioselective Ca-
talysis with Transition Metal Compounds; VCH Verlagsgesellschaft:
Weinheim, 1993; Vol. 2, Ligands-References, p 359.
(2) (a) Ojima, I. Ed. Catalytic Asymmetric Synthesis; VCH: New
York, 1993. (b) Sheldon, R. A. Chirotechnology, Marcel Dekker: New
York, 1993. (c) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
J ohn Wiley & Sons: New York, 1994. (d) J acobsen, E. N.; Pfaltz, A.;
Yamamoto, H. Comprehensive Asymmetric Catalysis I-III; Springer:
New York, 1999.
(3) Kagan, H. B.; Dang, T.-P. J . Am. Chem. Soc. 1972, 94, 6429.
(4) (a) Knowles, W. S.; Sabacky, M. J .; Vineyard, B. D. J . Chem.
Soc., Chem. Commun. 1972, 10. (b) Vineyard, B. D.; Knowles, W. S.;
Sabacky, M. J .; Bachman, G. L.; Weinkauff, D. J . J . Am. Chem. Soc.
1977, 99, 5946.
(5) Fryzuk, M. D.; Bosnich, B. J . Am. Chem. Soc. 1977, 99, 6262.
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1981, 103, 2273.
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Yoda, N. Tetrahedron Lett. 1980, 21, 1051.
(8) Nagel, U.; Kinzel, E.; Andrade, J .; Prescher, G. Chem. Ber. 1986,
119, 3326.
(9) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souchi, T.; Noyori, R. J . Am. Chem. Soc. 1980, 102, 7932. (b) Miyashita,
A.; Takaya, H.; Souchi, T.; Noyori, R. Tetrahedron 1984, 40 1245. (c)
Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.;
Takemomi, T.; Akutagawa, S.; Noyori, R. J . Org. Chem. 1986, 51, 629.
(10) (a) Burk, M. J .; Feaster, J . E.; Harlow, R. L. Organometallics
1990, 9, 2653. (b) Burk, M. J . J . Am. Chem. Soc. 1991, 113, 8518. (c)
Burk, M. J .; Feaster, J . E.; Nugent, W. A.; Harlow, R. L. J . Am. Chem.
Soc. 1993, 115, 10125. (d) Burk, M. J .; Lee, J . R.; Martine, J . P. J .
Am. Chem. Soc. 1994, 116, 10847. (e) Burk, M. J .; Wang, Y. M.; Lee,
J . R. J . Am. Chem. Soc. 1996, 119, 5142.
(11) (a) Zhu, G.; Cao, P.; J iang, Q.; Zhang, X. J . Am. Chem. Soc.
1997, 119, 1799. (b) Zhu, G.; Zhang, X. J . Org. Chem. 1998, 63, 3133.
(c) Zhu, G.; Zhang, X. J . Org. Chem. 1998, 63, 9591. (d) Cao, P.; Zhang,
X. J . Am. Chem. Soc. 1999, 121, 7708.
(12) (a) J iang, Q.; J iang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew.
Chem., Int. Ed. Engl. 1998, 37, 1100. (b) J iang, Q.; Xiao, D.; Zhang,
Z.; Cao, P.; Zhang, X. Angew. Chem., Int. Ed. Engl. 1999, 38, 516. (c)
Zhang, Z.; Zhu, G.; J iang, Q.; Xiao, D.; Zhang, X. J . Org. Chem. 1999,
64, 1774.
(13) (a) Fryzuk, M. D.; Bosnich, B. J . Am. Chem. Soc. 1978, 100,
5491. (b) Slack, D. A.; Greveling, I.; Baird, M. C. Inorg. Chem. 1979,
18, 3125. (c) Bosnich, B.; Roberts, N. K. Adv. Chem. Ser. 1982, 196,
337. (d) Bacos, J .; Toth, I.; Heli, B.; Szalontai, G.; Parkanyi, L.; Fulop,
V. J . Organomet. Chem. 1989, 370, 263. (e) Trabesinger, G.; Albinati,
A.; Feiken, N.; Kunz, R. W.; Pregosin, P. S.; Tschoener, M. J . Am.
Chem. Soc. 1997, 119, 6315.
(14) (a) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106. (b) Oliver, J .
D.; Riley, D. P. Organometallics 1983, 2, 1032. (c) Brown, J . M.; Evans,
P. L. Tetrahedron, 1988, 44, 4905. (d) Giovannetti, J . S.; Kelly, C. M.;
Landis, C. R. J . Am. Chem. Soc. 1993, 115, 4040. (e) Brunner, H.;
Winter, A.; Breu, J . J . Organomet. Chem. 1998, 553, 285.
(15) Kagan, H. B.; Fiaud, J . C.; Hoornaert, C.; Meyer, D.; Poulin, J .
C. Bull. Soc. Chim. Belg. 1979, 88, 923.
10.1021/jo0004613 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/17/2000

5872 J . Org. Chem., Vol. 65, No. 18, 2000
Notes
Sch em e 1a
a
Key: (a) (i) acetone, H2SO4, 81%, (ii) AcOH, H2O, 40 °C, 2.5 h, 78%; (b) BzCl, pyridine, CH2Cl2, -78 °C; (c) TsCl, pyridine, DMAP,
0 °C, 4 h; (d) K2CO3, CH3OH, rt, 65% from 5; (e) LiEt3BH, THF, 0 °C, 83%; (f) MsCl, Et3N, CH2Cl2, 0 °C, 96%; (g) Ph2PH, n-BuLi, THF,
0 °C to rt, 67%.
Ta ble 1. Asym m etr ic Hyd r ogen a tion of En a m id e 11a Ca ta lyzed by a Rh od iu m Bisp h osp h in e Com p lexa
entry
catalyst
solvent
H2 (bar)
eeb (%)
confignc
1d
2d
3d
4d
5d
6g
7
[RhCl(C2H4)2]2/(+)-DIOP
[RhCl(C2H4)2]2/(+)-DIOP
[RhCl(C2H4)2]2/(+)-DIOP
[Rh(COD)(+)-DIOP]ClO4
[Rh(COD)(+)-DIOP]ClO4
[Rh(COD)Cl]2/3
[Rh(COD)Cl]2/3
[Rh(COD)Cl]2/3
[Rh(COD)Cl]2/3
[Rh(COD)Cl]2/3
[Rh(COD)2SbF6/3
[Rh(COD)2SbF6/3
[Rh(COD)2SbF6/3
[Rh(COD)2SbF6/(+)-DIOP
[Rh(COD)2SbF6/2
EtOH
1.1
1.1
1.1
1.1
1.1
1.1
10
50
10
10
1.1
10
42.5e
45e
R
R
S
EtOH/benzene (2/1)
benzene
EtOH
benzene
MeOH
MeOH
MeOH
CH2Cl2
toluene
MeOH
44e
38.5e
68e
94.0
97.8
91.6
31.5
5.4
98.8
98.3
97.2
51.6
17.3
R
R
R
R
R
R
R
R
R
R
R
S
8
9
10
11f
12
13
14g
15
MeOH
MeOH
MeOH
MeOH
50
1.1
10
a
The reaction was carried out at rt under H2 for 60 h. The catalyst was made in situ by stirring a solution of a Rh precusor and the
bisphosphine ligand in solvent 3 mL [[substrate (0.25 mmol, 0.083 M)/[RH]/L ) 1:0.02:0.022]]. The reaction went with >99% conversion
b
unless stated otherwise. Enantiomeric excesses were determined by chiral GC using a Supelco Chiral Select 1000 column (0.25 mm ×
d
15 m). c The absolute configuration was assigned by comparison of optical rotation with reported data. These results are from ref 20.
e The ee’s were determined by optical rotation. f In entries 6 and 11, 20% and 35% conversion was achieved by GC analysis, respectively.
g
The reaction proceeded with >99% conversion in 24 h.
we are pleased to report that the Rh-3 complex leads to
extremely high enantioselectivity for hydrogenation of
enamides.
The synthetic route for ligand 3 (R,S,S,R)-DIOP* is
shown in Scheme 1. Cheap, commercially available
D-mannitol 4 was used as the starting material. D-
mannitol 4 is first converted to 3,4-O-isopropylidene-D-
mannitol 5 followed by dibenzoylation (5 f 6) and
ditosylation (6 f 7). Transesterification of 7 followed by
an intramolecular SN2 reaction gives 8 with inversion of
configuration of the two stereogenic centers.18 Reduction
of the diepoxide 8 affords the desired chiral diol 9.19
Bismesylate 10 was formed smoothly and nucleophilic
attack of 10 with diphenylphosphine in the presence of
n-BuLi produces 3 as a colorless oil in 67% yield. An
advantage of this synthetic route is the versatility of the
diepoxide 8. Nucleophilic opening of the diepoxide 8 with
various metal reagents (e.g., RMgBr) can lead to many
enantiomerically pure 1,4-diols.19
We have applied ligand 3 (R,S,S,R)-DIOP* for rhodium-
catalyzed asymmetric hydrogenation of enamides. The
active catalyst employed in our study was generated in
situ from a neutral Rh complex [Rh(COD)Cl]2 or a
cationic Rh complex [Rh(COD)2]SbF6 with 3 (R,S,S,R)-
DIOP* (1:1.1). Enamide 11a was chosen as a typical
substrate to screen reaction conditions (Table 1). Both
neutral (entries 6-8) and cationic Rh complexes (entries
(16) We name the ligand as DIOP* to dedicate Professor Kagan’s
landmark contribution of metal-DIOP-catalyzed asymmetric reactions
(ref 3). The result was presented in ChiraSource′99 in Philadephia,
Nov 16, 1999, and this paper was submitted for publication in a
different journal after the meeting. During this process, RajanBabu
et al.24d independently reported the synthesis of 3 and its application
in Pd-catalyzed asymmetric allylic alkylation albeit with a low ee.
(17) Related conformational studies show that substituents located
in axial positions cause erosion of enantioselectivity while equatorial
substituents lead to a more effective chiral catalyst in some chiral
phosphine systems: (a) Michalik, M.; Freier, T.; Schwarze, M.; Selke,
R. Magn. Reson. Chem. 1995, 33, 835. (b) Selke, R.; Ohff, R.; Riepe, A.
Tetrahedron 1996, 52, 15079.
(18) Marrer, Y. L.; Dureault, A.; Greck, C.; Micas-Languin, D.;
Gravier, C.; Depezay, J .-C. Heterocycles 1987, 25, 541.
(19) Allevi, P.; Anastasia, M.; Ciuffreda, P.; Sanvito, A. M. Tetra-
hedron: Asymmetry 1994, 5, 927.

Notes
J . Org. Chem., Vol. 65, No. 18, 2000 5873
Ta ble 2. Asym m etr ic Hyd r ogen a tion of En a m id es 11
Ca ta lyzed by a Rh od iu m -3 Com p lexa
tion conditions (entry 12, Table 1). An important feature
of the Rh-3 (R,S,S,R)-DIOP* catalyst is its high enan-
tioselectivity for hydrogenation of an R-aryl enamide
containing a â-alkyl group (entries 11-16). An isomeric
mixture of (Z)- and (E)-enamides was reduced with high
enantioselectivities. The enantioselectivities achieved in
the Rh-3-catalyzed hydrogenation of enamides are com-
parable or better than those obtained with Rh-DuPhos,10e
Rh-BICP,11c Rh-Binaphane,22 and Rh-aminophenylphos-
phine systems.23 However, we found that enantioselec-
tivities (<90% ee) are much lower for hydrogenation of
N-acyl dehydroamino acids with the Rh-3 catalyst. The
detailed reason for these results is still not clear.
In summary, a new bisphosphine ligand 3 (R,S,S,R)-
DIOP* was developed as an effective ligand for Rh-
catalyzed hydrogenation of enamides providing an effi-
cient way to prepare chiral amines. A dramatic solvent
effect has been observed. The concept of ligand confor-
mational analysis has been illustrated and will be useful
for future ligand design. (R, S, S, R)-DIOP* and its
derivatives can be prepared easily from the readily
available D-mannitol24 and this type of ligands may be
useful for many highly enantioselective catalytic reac-
tions.
entry
Ar
C6H5
R
Rh
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15d
16
H
H
H
H
H
H
H
H
H
H
[Rh(COD)Cl]2
97.8
98.3
97.6
97.7
98.5
C6H5
[Rh(COD)2]SbF6
[RH(COD)Cl]2
[Rh(COD)2]SbF6
[Rh(COD)Cl]2
[Rh(COD)2]SbF6
[Rh(COD)Cl]2
p-CF3C6H4
p-CF3C6H4
m-CH3C6H4
m-CH3C6H4
p-PhC6H4
p-PhC6H4
2-naphthyl
2-naphthyl
C6H5
C6H5
C6H5
p-CF3C6H4
p-MeOC6H4
2-naphthyl
98.8
>99c
>99c
>99c
99.0c
97.3
[Rh(COD)2]SbF6
[Rh(COD)Cl]2
[Rh(COD)2]SbF6
[Rh(COD)2]SbF6
[Rh(COD)2]SbF6
[Rh(COD)2]SbF6
[Rh(COD)2]SbF6
[Rh(COD)2]SbF6
[Rh(COD)2]SbF6
CH3
isopropyl
Bn
CH3
CH3
99.0
98.6c
98.3
98.0c
>99c
CH3
a
The reaction was carried out at rt under 10 bar of H2 for 48-
60 h. The catalyst was made in situ by stirring a solution of a Rh
precusor and the bisphosphine ligand 3 in 3 mL of methanol
[[substrate (0.25 mmol, 0.083 M)/[RH] / 3 ) 1:0.02:0.022]]. The
reaction went with >99% conversion unless stated otherwise.
Exp er im en ta l Section s
b
Enantiomeric excesses were determined by chiral GC using a
Supelco Chiral Select 1000 column (0.25 mm × 15 m). The R
absolute configuration was assigned by comparing optical rotation
with reported data. c Enantiomeric excesses were determined by
chiral HPLC using a (S,S)-whelk-O1 column. With 20% conver-
sion based on GC analysis.
Gen er a l Meth od s. All reactions and manipulations were
performed in
a nitrogen-filled glovebox or using standard
Schlenk techniques. Toluene, tetrahydrofuran (THF) and hex-
anes were distilled from sodium benzophenone ketyl under
nitrogen. Methylene chloride (CH2Cl2) was distilled from CaH2.
Methanol (CH3OH) was distilled from Mg under nitrogen. Gas
chromatography was carried out on Helwett-Packard 6890 gas
chromatograph using a Chiral Select 1000 column (Dimen-
sions: 15 m × 0.25 mm), carrier gas: He (1 mL/min-1). HPLC
analysis was carried out on a Waters 600 chromatograph with
an (S,S)-Whelk-01 column from Regis Technologies, Inc. [particle
size: 5.0 µm. column dimensions: 25 cm (length) × 0.46 cm
(i.d.)].
d
11-13) with 3 are highly enantioselective for hydrogena-
tion of 11a in MeOH. Increasing H2 pressure allowed
higher conversion albeit with slight erosion of enanti-
oselectivity (entries 6-8 and entries 11-13). The most
dramatic observation was the solvent effect. Changing
from methanol to CH2Cl2 and toluene, reduced the ee
significantly from 97.8% to 31.5% and 5.4%, respectively
(entries 7, 9, and 10). A similar solvent effect was
observed in Kagan’s studies. For example, asymmetric
hydrogenation of 11a catalyzed by a Rh-DIOP complex
gave 42.5% ee (R) in EtOH (entry 1) and 44% ee (S) in
benzene (entry 3).20a It has been suggested that such
effects are the results of conformational changes of the
metal complex in different solvents.21 Based on this
assumption, we speculated one conformation of a Rh-3
complex must be stable and highly effective for chiral
recognition in methanol. All substituents are located in
equatorial positions may be the reason that 3 is an
excellent chiral ligand. The optimal conditions for hy-
drogenation 11a with Rh-3 are shown in entry 12. Under
these reaction conditions, hydrogenation of 11a catalyzed
by a Rh-(+)-DIOP and an Rh-2 species gave 12a in
51.6% ee (R) (entry 14) and 17.3% ee (S) (entry 15),
respectively. The subtle change of ligand structure indeed
results in a huge difference in the hydrogenation reaction.
The scope of the asymmetric hydrogenation reaction
with different substrates is shown in Table 2. High
enantioselectivities (97-99% ee) were achieved for hy-
drogenation of R-aryl enamides using the optimal reac-
Syn th esis of 3,4-O-Isop r op ylid en e-(3S, 4S)-d ih yd r oxy-
(2S,5S)-h exa n ed iol Bis(m eth a n esu lfon a te) 10. To a solution
of 3,4-O-isopropylidene-(3S,4S)-dihydroxy-(2S,5S)-hexanediol (2.2
g, 11.6 mmol) and triethylamine (4.9 mL, 34.8 mmol) in CH2Cl2
(30 mL) was added dropwise a solution of methanesulfonyl
chloride (2.0 mL, 25.8 mmol) in CH2Cl2 (10 mL) at 0 °C. After
30 min at 0 °C, the reaction mixture was stirred for an additional
30 min at room temperature then quenched by saturated
aqueous NH4Cl solution. The aqueous layer was extracted with
CH2Cl2 and the combined organic solution was dried over Na2-
SO4. After evaporation of the solvent, the residue was purified
by flash chromatography on silica gel eluting with CH2Cl2/Et2O
(9/1) to give a colorless oil 3.85 g in 96% yield: [R]24 ) -1.3° (c
D
) 1.04, CHCl3); 1H NMR (CDCl3, 360 MHz) δ 4.82-4.76 (m, 2H),
3.99-3.96 (m, 2H), 3.03 (s, 6H), 1.45 (d, J ) 6.6, 6 Hz), 1.37 (s,
6H); 13C NMR (CDCl3, 90 MHz) δ 110.14, 78.19, 76.26, 38.53,
26.75, 17.63; HRMS calcd for C11H23O8S2 (MH+) 347.0834 and
C11H22O8S2Na (MNa+) 369.0654, found 347.0834 and 369.0654.
Syn th esis of 3,4-O-Isop r op ylid en e-(3S,4S)-d ih yd r oxy-
(2R,5R)-bis(d ip h en ylp h osp h in o)h exa n e
3 [(R,S,S,R)-DI-
OP *]. To a solution of diphenylphosphine (1.15 mL, 6.6 mmol)
in THF (50 mL) was added n-BuLi in hexane (4.0 mL, 6.4 mmol)
(22) Xiao, D.; Zhang, Z.; Zhang, X. Organic Lett. 1999, 1, 1679.
(23) F.-Y. Zhang, C.-C. Pai, A. S. C. Chan, J . Am. Chem. Soc. 1998,
120, 5808.
(24) For some recent chiral phosphine ligands made from D-
mannitol, see: (a) Holz, J .; Quirmbach, M.; Schmidt, U.; Heller, D.;
Sturmer, R.; Borner, A. J . Org. Chem. 1998, 63, 8031. (b) Carmichael,
D.; Doueet, H.; Brown, J . M. Chem. Commun. 1999, 261. (c) Li, W.;
Zhang, Z.; Xiao, D.; Zhang, X. Tetrahedron Lett. 1999, 40, 6701. (d)
Yan, Y.-Y.; RajanBabu, T. V. Org. Letter 2000, 2, 199. (e) Yan, Y.-Y.;
RajanBabu, T. V. J . Org. Chem. 2000, 65, 900. (f) Li, W.; Zhang, Z.;
Xiao, D.; Zhang, X. J . Org. Chem. 2000, 65, 3489.
(20) (a) Kagan, H. B.; Langlois, N.; Dang, T. P. J . Organomet. Chem.
1975, 90, 353. (b) Sinou, D.; Kagan, H. B. J . Organomet. Chem. 1976,
114, 325 (up to 92% ee was observed with a Rh-DIOP catalyst for
hydrogenation of a substrate listed in entry 11, Table 2).
(21) Bakos, J .; Toth, I.; Heli, B.; Szalontai, G.; Parkanyi, L.; Fulop,
V. J . Organomet. Chem. 1989, 370, 263.

5874 J . Org. Chem., Vol. 65, No. 18, 2000
Notes
at -78 °C over 5 min via syringe. The resulting orange solution
was warmed to room temperature and stirred for 1 h. After
cooling the mixture to -78 °C, 3,4-O-isopropylidene-(3S,4S)-
dihydroxy-(2S,5S)-hexanediol bis(methanesulfonate) 10 (1.04 g,
3.0 mmol) in THF (20 mL) was added over 20 min. The resulting
orange solution was warmed to room temperature and stirred
overnight. The white suspension was hydrolyzed with saturated
aqueous NH4Cl solution. The aqueous layer was extracted with
CH2Cl2 and the combined organic solution was dried over
anhydrous Na2SO4. After removal of the solvents under reduced
pressure, the residue was purified by flash chromatography on
silica gel eluting with hexanes/ethyl acetate (95/5) to give a
Gen er a l P r oced u r e for Asym m etr ic Hyd r ogen a tion . To
a solution of a rhodium precursor (0.005 mmol) in methanol (3
mL) in a glovebox was added a bisphosphine (0.055 mL of 0.1
M solution in toluene, 0.0055 mmol). After the mixture was
stirred for 10 min, an enamide (0.25 mmol) was added. The
hydrogenation was performed at room temperature under 1.1-
50 bar of hydrogen for 24-60 h. The hydrogen was released and
the reaction mixture was passed through a short silica gel
column to remove the catalyst. The enantiomeric excess was
measured by GC or HPLC directly without any further purifica-
tion. The absolute configuration of the products was determined
by comparing the observed rotation with the reported value.22
colorless oil 1.06 g in 67% yield: [R]24 ) +41.8° (c ) 0.88,
D
toluene); 1H NMR (CDCl3, 360 MHz) δ 7.56-7.52 (m, 8H), 7.38-
7.33 (m, 12H), 3.78-3.76 (m, 2H), 2.50-2.46 (m, 2H), 1.14 (s,
6H), 0.91 (d, J ) 7.0 Hz, 3H), 0,87 (d, J ) 6.9 Hz, 3H); 13C NMR
(CD2Cl2, 90 MHz) δ 137.46 (d, J ) 15.9 Hz), 137.03 (d, J ) 15.5
Hz), 134.14 (d, J ) 3.7 Hz), 133.91 (d, J ) 4.0 Hz), 129.30 (d, J
) 8.6 Hz), 128.75 (d, J ) 7.1 Hz), 108.27, 77.2 (dd, J 1) 12.0 Hz
J 2 ) 6.8 Hz), 31.33 (d, J ) 14.3 Hz), 27.05, 10.74 (d, J ) 17.6
Hz); 31P NMR (CDCl3) δ ) -6.3 ppm; HRMS calcd for C33H37O2P2
(MH+) 527.2269, found 527.2271.
Ack n ow led gm en t. This work was supported by a
NIH grant. We acknowledge a generous loan of precious
metals from J ohnson Matthey Inc. and a gift of chiral
GC columns from Supelco.
J O0004613